Background: Pancreatic cancer (PaCa) is the third leading cause of cancer death in the United States despite its low incidence rate, owing to a 5-year survival rate of 10%. It is often asymptomatic in early stage, resulting in the majority of diagnoses occurring when cancer has already metastasized to distant organs. Late diagnosis deprives patients of potentially curative treatments such as surgery and impacts survival rates. Diabetes can be an early symptom of PaCa. Indeed, 25% of PaCa patients had a preceding diabetes diagnosis. Among all people with new onset diabetes (NOD), 0.85% will be diagnosed with PaCa within 3 years, which represents 6-8 fold increased risk for PaCa compared to the general population. Surveillance of the NOD population for PaCa presents an opportunity to shift PaCa diagnosis to earlier stage by finding it sooner. Methods: Whole blood was obtained from a cohort of 117 PaCa patients as well as 800 non-cancer controls with and without NOD. Plasma was processed to isolate cfDNA and 5hmC and low pass whole genome libraries were generated and sequenced. The EpiDetect assay combines 5hmC and whole genome sequencing data and were generated using Bluestar Genomics’s technology platform. Results: To investigate whether PaCa can be detected in plasma, we interrogated plasma-derived cfDNA epigenomic and genomic signal from PaCa patients and non-cancer controls. We first trained stacked ensemble models on PaCa and non-cancer samples utilizing 5hmC, fragmentation and CNV-based biomarkers from cfDNA. These models performed stably with a median of 72.8% sensitivity and 90.1% specificity measured across 25 outer fold iterations using the training data set, which was composed of 50% early stage (Stages I & II) disease. The final binomial ensemble model was trained using all of the training data, yielding an area under the receiver operating characteristic curve (auROC) of 0.9, with 75% sensitivity and 89% specificity. This model was then tested on an independent validation data set from 33 PaCa patients (24 with diabetes, 15 of which was NOD) and 202 non-cancer control patients (76 with diabetes, 51 of which was NOD) and yielded a classification performance auROC of 0.9 with 67% sensitivity at 92% specificity. Lastly, model performance in the subset of patient cohort with NOD only had an auROC of 0.87 with 60% sensitivity at 88% specificity. Conclusions: Our results indicate that 5hmC profiles along with CNV and fragmentation patterns from cfDNA can be used to detect PaCa in plasma-derived cfDNA. Overall, model performance was stable and consistent between the training and independent validation datasets. A larger clinical study is under development to investigate the utility of the model described in this pilot study in identifying occult PaCa within the NOD population, with the aim of shifting diagnosis to early stage and potentially improving patient outcomes.